Reaction products of 4, 6-diamino-5-nitrosopyrimidines with alkyl benzoylacetates, and process of obtaining the same



3,267 102 REACTION PRODUCTS oi 4,6-DlAMlN-5-NITRO- SOPYRIMIDINES wrrn ALKYL BENZOYLACE- 3,267,102 Patented August 16, 1966 EXAMPLE I Preparation of 4-aminc-2,7-diphenyl-6-pteridinecarboxylic acid, ethyl ester TATES, AND PROCESS OF OBTALNING THE An intimate mixture of 10 g. of 4,6-diamino-5-nitroso- 5 SAME Z-phenylpyrimidine and 20 g. of ethyl benzoylacetate Thomas Osdenea Richmofld assign to Amencan were placed into a large tube which was immersed into an g gg CmpmatmnNeW acorpo' oil bath maintained at 150. A vigorous evolution of g ilg g f gsgg Oct 23 1965 Sen N0. 504 131 vapor quickly started. The tube was heated for 3 hours 9 Claims i 10 and, after cooling, 20 ml. of ethanol were added and the solid was removed by filtration. Recrystallization from This invention is directed to novel reaction products h l afforded -l p i -P obtained by reacting 4,6-diamino-5-nitrosopyrimidines V acldnethyl ester, 217-218 with alkyl benzoylacetates, and to a novel process for Y -C I J C, 67.91; H, 4.61; N, 18.82. Found: obtaining said products. Depending upon the reaction C, 67-71; 4-50; N, goiditionls usectli in the 6process, the pbrodulcts arg either A PLE 11 enzoy pteri ines or -pteri ine car oxy ic aci esters. I

As determined by standard pharmacological procedures eparagon f f' '5! ,2 01] 2 DJ henyl' with warm-blooded animals, the claimed compounds 'pten mean my [C H y ester ShOW diuretic and antiviral properties. These compounds 20 A mixture of 5 g. of 4,6-diamino-2-(p-chlorophenyl)- can be formulated conventionally in unit dosage forms S-nitrosopyrimidine and 10 ml. of ethyl benzoylacetate by mixing with various carriers and excipients. were heated in an oil bath at 150 for mins. A fur- The process and the compounds of the invention can ther 5 ml. of ethyl benzoylacetate was added, the temperbe characterized by the following reaction scheme: ature was raised to 170 and the mixture was maintained NH (302R arm H o N 002R N NO A I G 150 180 I y NHZ R2 Re N NAA \200 or above A NHZ where R is ethyl or methyl; R is phenyl, 2-thienyl or phenyl substituted by halogen, lower alkyl, lower alkoxy or trifluoromethyl; and R is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl.

Referring now to the above reaction scheme, the compounds of the present invention are prepared by mixing a 4,6-diamino-5-nitrosopyrim idine 1) with an alkyl ben- Zoylacetate (2), and placing the mixture in a vessel which is immersed in an oil bath. If alkyl esters of 6-pteridinecarhoxylic acid (3) are desired, the oil bath temperature is maintained at 150 to 180 C. for a sufficient time to substantially complete the reaction. The reaction mixture is cooled and an alkanol solvent, preferably ethanol, is added. The precipitate which results is filtered and can be purified from ethanol.

Where a 6-benzoylpteridine (4) is desired, the above procedure is varied to the extent that the reactants are heated to 200 C. for only about an hour.

Generally a mixture of both products is obtained and these may be separated from one another by extracting the reaction mixture with boiling ethanol to remove the acid product leaving the other as a solid.

The invention is further illustrated by the following examples.

in the bath for 3 hrs, after which a further 5 ml. of ester was added and the temperature of the bath was raised to After 3 hrs. at that temperature, the mixture was treated with 20 ml. of ethanol and allowed to stand. The solid obtained was removed by filtration and the material was recrystallized from ethanol to afford 4-amino-2-(pchlorophenyl)-7-phenyl-6-pteridinecarboxylic acid, ethyl ester, M.P. 250251.

Analysis.Calc.: C, 62.15; H, 3.97; N, 17.26; Cl, 8.74. Found: C, 61.98; H, 3.89; N, 17.24; Cl, 9.0.

EXAMPLE III Preparation of 4-amin0-6-benzoyl-7-hydr0xy- Z-phenylpteridine A mixture of 10 g. of 4,6-diamino-5-nitroso-2-phenylpyrimidine and 20 g. of ethyl benzoylacetate was heated for 1 hr. in an oil bath maintained at 200. About 30 ml. of ethanol were added and the solid formed was removed by filtration. This solid was extracted with 250 ml. of boiling ethanol to remove any of the other product formed and the residue was recrystallized from aqueous 2-ethoxyethanol to aiford 4-amino-6-benzoyl-7- hydroxy-Z-phenylpteridine, M.P. 3l73l8.

A1zalysis.Ca1c.: C, 66.46; H, 3.82; N, 20.40. Found: C, 66.30; H, 3.97; N, 20.02.

3 EXAMPLE IV Preparation of 4-amino-6-benz0yl-2-(p-chlorophenyl)- 7-hydroxy-pteridine Reaction of 4,6-diamino-2-(p-chlorophenyl)-5-nitrosopyrimidine with ethyl benzoylacetate carried out as in Example III afforded 4-amino-6-benzoyl-2-(p-chlorophenyl)-7-hydroxypteridine, M.P. 354.

Analysis.-Calc.: C, 60.41; H, 3.20; N, 18.54; Cl, 9.38. Found: C, 60.08; H, 3.14; N, 18.67; Cl, 9.57.

EXAMPLE V Condensation of 4,6-diamino-5-nitroso-2-(Z-thienyl)pyrimidine with ethyl benzoylacetate at ISO-160, carried out as in Example I, gives 4-amino-7-phenyl-2-(2-thienyl)-6-pteridinecarboxylic acid, ethyl ester.

EXAMPLE VI Condensation of 4,6-diamino-5-nitroso-2-(p-tolyl)pyrimidine with ethyl p-chlorobenzoylacetate at ISO-160, carried out as in Example II, gives 4-amino-7-(p-chlorophenyl)-2-(p-tolyl)-6-pteridinecarboxylic acid, ethyl ester.

EXAMPLE VII Condensation of 4,6-diamino-5-nitroso-2-(m-trifiuoromethylphenyl) pyrimidine with methyl benzoylacetate, as carried out in Example I, gives 4-amino-7-phenyl-2-(mtrifluoromethylphenyl)-6-pteridinecarboxylic acid, methyl ester.

EXAMPLE VIII Condensation of 4,6-diamin-2-(p-methoxyphenyl)-5- nitrosopyrimidine with ethyl m-toluoylacetate, as carried out in Example 11, gives 4-amino-2-(p-methoxyphenyl)-7- (m-tolyl)-6-pteridinecarboxylic acid, ethyl ester.

EXAMPLE IX Reaction of 4,6 diamino nitroso 2 (o-tolyl)- pyrimidine with ethyl benzoylacetate at 200220, as de scribed in Example III, gives 4-amino-6-benzoyl-7-hydroxy-Z- o-tolyl pteridine.

EXAMPLE X Reaction of 4,6-diamino-2-(p-bromophenyl)-5-nitrosopyrimidine with ethyl p-trifluoromethylbenzoylacetate at 200220, as described in Example Ill, gives 4-amino-2- (p-bromophenyl) 7 hydroxy 6 (p trifiuoromethylbenzoyl)pteridine.

EXAMPLE XI Reaction of 4,6-diamino-2-(3,4-dichlorophenyl)-5-nitrosopyrimidine with ethyl benzoylacetate at 200220, as described in Example 111, gives 4-amino-2-(3,4-dichlorophenyl)-6-benzoyl-7-hydroxypteridine.

When the compounds of the invention are employed as diuretics and antiviral agents, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing conventional excipients, or in the form of solutions; or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to make the solutions isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects, and preferably at a level that is in the range of from about 0.5 gm. to about 1.0 gm. per kg. of body weight per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 700 mg. to about 900 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results.

I claim:

1. A compound of the formula:

ITlHz wherein R is phenyl, halophenyl, thienyl, lower alkylphenyl, lower alkoxyphenyl, halo(lower) or alkylphenyl, X is COOR where R is methyl or ethyl; or COR where R is phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl or hal-oalkylphenyl; Z is hydroxy or R 2. 4 amino 2,7 diphenyl 6 pteridinecarboxylic acid, ethyl ester.

3. 4 amino 2 (p chlorophenyl) 7 phenyl 6- pteridinecarboxylic acid, ethyl ester.

4. 4 amino 6 benzoyl 7 hydroxy 2 phenylpteridine.

5. 4 amino 6 benzoyl 2 (p chlorophenyl) 7- hydroxy-pteridine.

6. A method of preparing a mixture or at least two of the compounds of the group claimed in claim 1, wherein one compound is an alkyl ester of 6-pteridinecarboxylic acid and the other compound is a 6-benzoylpteridine, which comprises:

heat-reacting a 4,6-diamine-5-nitrosopyrimidine of the formula:

ITIH

N NO R]\\\\N/ NH- wherein R is as defined in claim 1,

with an alkyl benzoylacetate of the formula:

COsR 1129) wherein R and R are as defined in claim 1,

at a temperature within the range of from about C. to about 200 C.

7. A method as defined in claim 6 wherein:

the reaction mixture formed is cooled, an alkanol is added thereto, and then said two compounds are separated from each other.

8. A method as defined in claim 6 wherein:

the heat-reaction is performed in the temperature range of from about 150 C. to about 180 C. until the reaction is substantially completed, and then the alkyl ester of 6-pteridinecarboxylic acid is isolated as a precipitate.

9. A method as defined in claim 6 wherein:

the heat-reaction is performed at a temperature of about 200 C. for only about .an hour, and the resulting 6-benzoylpteridine is separated from the acid product by extracting the latter from the reaction mixture with a boiling alkanol solvent to leave the 6-benzoylpteridine as a solid.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner. 

1. A COMPOUND OF THE FORMULA: 